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Background: Leishmaniasis is a widespread skin protozoan infectious disease. It is an intracellular parasitic microorganism that develops in the body of infected female phlebotomine sandflies vector, prior to its transmission to human or animal host by the vector bite. The objective of this review is to highlight the current prevalence of Leishmaniasis in the Kingdom of Saudi Arabia, and the direction in research for its control. Materials: The update literature covered The infection of the host with this trypanosome starts with a skin bite from the infected sand fly, followed by penetration of the parasite into cellular structures of the skin, or its infiltration to the circulatory system, targeting the internal organs. Different research groups are experimenting on construction of recombinant Leishmania antigens, compiled from this protozoa and from antigens recovered from the saliva of sand flies, in an attempt to immunize the host for protection against this disease.Conclusion: The benefits behind such a review is to support the personnel involved in developing evidence-based policy guidelines, strategies and standards for disease prevention and management of their implementation; in addition, it provided a technical support to member states to collaborate on establishment of an effective systems to handle the Leishmaniasis. Keywords: Review; Leishmaniasis; prevalence; control; Saudi Arabia.

Statins trigger apoptotic cell death in some types of growing tumor cells in a cholesterol-lowering-independent manner. Self-nanoemulsifying delivery systems (SNEDs) are potentially effective for the suppression of breast cancer development. This study aims to investigate the potential anticancer activity of fluvastatin (FLV)-SNEDs in breast cancer while comparing it with FLV in vitro as well as in vivo exploiting/using MDA-MB-231 and Erhlich ascites carcinoma (EAC)-bearing mice, respectively. Biochemical analysis of liver and kidney functions, oxidative stress markers, and histopathological examinations of such tumor tissues were performed showing the potentiality of SNEDs as a nanocarrier for antitumor agents. FLV-SNEDs demonstrated more potent anticancer activity compared to FLV on MDA-MB-231 and hepatocellular carcinoma (HepG2) cells. In vivo experiments on the EAC-bearing mice model indicated that FLV and-to a greater extent-FLV-SNEDs ameliorated EAC-induced hepatotoxicity and nephrotoxicity. FLV or FLV-SNEDs evidently reduced the percent of Ki-67 +ve EAC cells by 57.5% and 86.5% in comparison to the vehicle-treated EAC group. In addition, FLV or FLV-SNEDs decreased Bcl-2 levels in serum and liver specimens. In contrast, FLV or FLV-SNEDs significantly activated the executioner caspase-3. Simultaneously, both FLV and FLV-SNEDs stimulated p53 signaling and modulated Bcl-2 protein levels in treated cells. Collectively, these results support the contribution of apoptotic cell death in mediating the anticancer activities of FLV and FLV-SNEDs against murine EAC model in vivo. This study provides new understandings of how FLV and FLV-SNEDs regulate EAC cell viability via upregulation of p53 signaling, and through modulation of cleaved caspase-3 as well as antiapoptotic Bcl-2 marker.

Luteolin is an excellent flavone possessing several beneficial properties such as antioxidant and anti-inflammatory effects which are interesting for skin delivery. Development of an appropriate skin delivery system could be a promising strategy to improve luteolin cutaneous performance.So, the main aim of this work was to fabricate, characterize and evaluate phospholipid-based luteolin-loaded lipid nanocapsules for skin delivery. The influence of phospholipid/oil ratio, surfactant type and chitosan coating were investigated. The prepared formulations underwent in vitro assessment and the selected formulations were evaluated ex vivo and in vivo. The mean diameters of investigated formulations varied between 174 nm and 628 nm while zeta potential varied between -25.7 ± 4.8 mV and 6.8 ± 1.7 mV. Increasing in phospholipid/oil ratios resulted in decrease in particles size with little effect on zeta potential and drug encapsulation. Cremophor EL showed the lowest particle sizes and the highest drug encapsulation. Chitosan coating shifted zeta potential towards positive values. Structural analyses showed that luteolin is incorporated into lipid core of nanocapsules. Selected formulations (LNC4 and LNC13) exhibited sustained in vitro release and antioxidant activity. LNC13 (chitosan coated) showed higher flux (0.457 ± 0.113 µg/cm

The effect of surface-modification of Tamoxifen (Tam)-loaded-niosomes on drug cytotoxicity and bio-distribution, via functionalization with chitosan and/or PEGylation, was investigated.Tam-loaded hybrid-nanocarriers (Tam-loaded niosomes, chitosomes, PEGylated niosomes, and PEGylated chitosomes) were formulated and characterized.Chitosanization with/without PEGylation proved to selectively enhance Tam-release at the cancerous-acidic micromilieu. Cytotoxic activity study showed that Tam-loaded PEGylated niosomes had a lower ICAll these results concluded the crucial effect of both PEGylation and chitosan-functionalization of Tam-loaded niosomes in enhancing effectiveness, targetability, and safety.

Fluvastatin (FLV) is a statin family member that may play a role in modulating a variety of medical disorders such as atherosclerosis and breast cancer. The present study addresses the ability of FLV to modulate the cellular immune response and provides a new nanosized FLV formula (self-nanoemulsifying delivery system, SNED) potentially more effective for suppression of breast cancer development. We monitored autophagic machinery through the expression of microtubule-associated protein 1A/1B-light chain 3 (LC3I/II). Lysosomal activity upon treatment was evaluated by mRNA and protein expression of lysosomal-associated membrane protein 1 (LAMP-1). Mitogen-activated protein kinase (MAPK) signaling and its association with proinflammatory cytokine secretion were assessed in treated cells. Autophagosome formation was significantly increased in cells that were pretreated with FLV-SNED in comparison to FLV-treated cells. Activation of autophagy was accompanied with arrest of LAMP-1 expression, which correlates with lysosomal activity. Simultaneously, both FLV and FLV-SNED activated MAPK signaling and modified interleukin-6 and tumor necrosis factor-α levels in treated cells. These findings indicate that FLV reduces cell viability via depletion of lysosomal activities along with accumulation of autophagosomes leading to disturbance of autophagosome-lysosomal fusion in treated cells. Furthermore, our data reveal the effectiveness of both FLV agents in the modulation of proinflammatory cytokine secretion from treated cells via regulation of MAPK signaling cascades and indicate that FLV-SNED is more efficient than FLV. This study provides new insights into how FLV regulates breast cancer cell viability via modulation of AMPK-mTOR and ERK-mTOR signaling, and through autophagosome formation accompanied by lysosomal degradation.

Khalid M El-Say,1,2 Raed I Felimban,3,4 Hossam H Tayeb,4,5 Adeel G Chaudhary,3,6 Abdelsattar M Omar,7– 9 Waleed Y Rizg,1,2 Fuad H Alnadwi,10 Fathy I Abd-Allah,11 Tarek A Ahmed1,2 1Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; 2Center of Research Excellence for Drug Research and Pharmaceutical Industries, Pharmaceutical Technology Unit, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; 3Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; 4Center of Innovation in Personalized Medicine (CIPM), 3D Bioprinting Unit, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; 5Center of Innovation in Personalized Medicine (CIPM), Nanomedicine Unit, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; 6Center of Innovation in Personalized Medicine (CIPM), King Abdulaziz University, Jeddah, 21589, Saudi Arabia; 7Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; 8Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, 11884, Egypt; 9Centre for Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah, Saudi Arabia; 10Department of Nuclear Engineering, Faculty of Engineering, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; 11Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, 11651, EgyptCorrespondence: Khalid M El-Say, Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia, Tel +966-58-293-4511, Fax +966 26951696, Email kelsay1@kau.edu.saIntroduction: This work was aimed to develop a Curcuma oil-based self-nanoemulsifying drug delivery system (SNEDDS) 3D-printed polypills containing glimepiride (GMD) and rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes as a model for metabolic syndrome (MS).Methods: Compartmentalized 3D printed polypills were prepared and studied in streptozotocin/poloxamer induced diabetic/dyslipidemic rats. The pharmacokinetic parameters of GMD and RSV in the prepared polypills were evaluated. Blood glucose level, lipid profile, antioxidant, and biochemical markers activities were investigated. Also, histopathological examination of the liver and pancreas was carried out. The atherosclerotic index, the area of islets of Langerhans, and liver steatosis lesion scores were calculated.Results: The developed SNEDDS-loaded GMD/RSV polypills showed acceptable quality control characteristics with a high relative bioavailability of 217.16% and 224.28% for GMD and RSV, respectively, when compared with the corresponding non-SNEDDS pills. The prepared polypills showed dramatic lowering in blood glucose levels and substantial improvement in lipid profile and hepatic serum biomarkers as well as remarkable decrease in serum antioxidants in response to Poloxamer 407 intoxication. The prepared polypills decreased the risk of atherosclerosis and coronary disease by boosting the level of high-density lipoprotein and lowering both triglyceride and low-density lipoprotein. Microscopic examination showed normal hepatic sinusoids and high protection level with less detectable steatosis in the examined hepatocytes. Normal size pancreatic islets with apparently normal exocrine acini and pancreatic duct were also noticed.Conclusion: This formulation strategy clearly shows the potential of the developed polypills in personalized medicine for treatment of patients with MS.Graphical Abstract: Keywords: 3D-printed tablets, Curcuma oil, glimepiride, metabolic syndrome, rosuvastatin, SNEDDS, nanotechnology

Fungal eye infections are caused mainly by an eye injury and can result in serious eye damage. Fluconazole (FLZ), a broad-spectrum antifungal agent, is a poorly soluble drug with a risk of hepatotoxicity. This work aimed to investigate the antifungal activity, ocular irritation, and transport of FLZ-loaded poly (ε-caprolactone) nanoparticles using a rabbit eye model. Three formulation factors affecting the nanoparticle’s size, zeta potential, and entrapment efficiency were optimized utilizing the Box-Behnken design. Morphological characteristics and antifungal activity of the optimized nanoparticles were studied. The optimized nanoparticles were loaded into thermosensitive in situ hydrogel and hydroxypropylmethylcellulose (HPMC) hydrogel ophthalmic formulations. The rheological behavior, in vitro release and in vivo corneal transport were investigated. Results revealed that the percentage of poly (ε-caprolactone) in the nanoparticle matrix, polymer addition rate, and mixing speed significantly affected the particle size, zeta potential, and entrapment efficiency. The optimized nanoparticles were spherical in shape and show an average size of 145 nm, a zeta potential of −28.23 mV, and a FLZ entrapment efficiency of 98.2%. The antifungal activity of FLZ-loaded nanoparticles was significantly higher than the pure drug. The developed ophthalmic formulations exhibited a pseudoplastic flow, prolonged the drug release and were found to be non-irritating to the cornea. The prepared FLZ pegylated nanoparticles were able to reach the posterior eye segment without eye irritation. As a result, the developed thermosensitive in situ hydrogel formulation loaded with FLZ polymeric nanoparticles is a promising drug delivery strategy for treating deep fungal eye infections.

This work aimed to develop a three-dimensional printed (3DP) tablet containing glimepiride (GLMP) and/or rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes. Curcumin oil was extracted from the dried rhizomes of Curcuma longa and utilized to develop a self-nanoemulsifying drug delivery system (SNEDDS). Screening mixture experimental design was conducted to develop SNEDDS formulation with a minimum droplet size. Five different semi-solid pastes were prepared and rheologically characterized. The prepared pastes were used to develop 3DP tablets using extrusion printing. The quality attributes of the 3DP tablets were evaluated. A non-compartmental extravascular pharmacokinetic model was implemented to investigate the in vivo behavior of the prepared tablets and the studied marketed products. The optimized SNEDDS, of a 94.43 ± 3.55 nm droplet size, was found to contain 15%, 75%, and 10% of oil, polyethylene glycol 400, and tween 80, respectively. The prepared pastes revealed a shear-thinning of pseudoplastic flow behavior. Flat-faced round tablets of 15 mm diameter and 5.6–11.2 mm thickness were successfully printed and illustrated good criteria for friability, weight variation, and content uniformity. Drug release was superior from SNEDDS-based tablets when compared to non-SNEDDS tablets. Scanning electron microscopy study of the 3DP tablets revealed a semi-porous surface that exhibited some curvature with the appearance of tortuosity and a gel porous-like structure of the inner section. GLMP and RSV demonstrated relative bioavailability of 159.50% and 245.16%, respectively. Accordingly, the developed 3DP tablets could be considered as a promising combined oral drug therapy used in treatment of metabolic disorders. However, clinical studies are needed to investigate their efficacy and safety.

The in vitro dissolution of Avanafil (AVA) is the rate-limiting step for its bioavailability. Also, it undergoes the first-pass metabolism, and its absorption is altered significantly in the presence of food. So, our study aimed to overcome the previous hurdles and improve the AVA bioavailability by its incorporation in the ultra-deformable nanovesicles, transfersomes (TRF), then loading these nanovesicles in transdermal films. The AVA-loaded TRF formulation was optimized using Draper-Lin small composite design (D-LSCD). The optimized AVA-loaded TRF was evaluated for quality attributes and assessed for skin permeation using a fluorescence laser microscope and for pharmacokinetic parameters after topical application on the rats. The optimized AVA-loaded TRF showed a vesicle size of 97.75 nm, a zeta potential of -28.83 mV, and entrapment efficiency of 95.14% with good deformability and release profile. The intense discoloration in the deep skin layers of the rats indicated the permeation efficiency of AVA-loaded TRF films. The pharmacokinetic parameters specified the augmented absorption extent with C

Background Injectable in situ gel (ISG) systems suffer from high initial drug release that may result in toxic effects. Objective This work aimed to develop an injectable sustained release rosuvastatin (RSV) ISG formulation with minimum initial drug burst and improved hyperlipidemic efficacy. Methods Six formulation factors that affect RSV release after 0.5, 2 and 24 hrs have been screened and the significant ones were optimized utilizing an experimental design tool. The optimum ISG formulation components were physicochemically characterized. Kinetic treatment, dissolution efficiency and mean dissolution time were investigated for the developed ISG formulations. Pharmacodynamic effects of the optimized ISG formulation were studied and compared to ISG formulation loaded with free RSV and to a marketed oral drug product. Results The concentration polylactide-co-e-caprolactone (25: 75), the surfactant hydrophilic lipophilic balance (HLB) and the ratio of surfactant to polyethylene glycol 400 were significantly affecting the release of RSV during the first 24 h. Physicochemical characterization demonstrated complete dispersion of RSV in the polymeric matrix with slight changes in the drug crystalline structure. The optimized formulation demonstrated acceptable syringeability, good flow rate and was able to extend the in vitro drug release for 34 days. The ISG formulations complied with Weibull model. Pharmacodynamic study revealed a sustained reduction in the lipid profile that lasted for 21 days with a marked decrease in the lipid level during the first 24 hrs from the ISG system loaded with free RSV. Conclusion The optimized RSV ISG formulation could be considered a promising strategy due to a reduction in dosing frequency and enhancement in hypolipidemic efficacy.

Background: Vinpocetine (VPN) is a synthetic derivative of the Vinca minor alkaloids. The drug is characterized by a short half-life, limited water solubility and high hepatic first-pass effect. The objective was to develop different lipid-based nanocarriers (NCs) loaded into a thermosensitive in situ gelling (ISG) system to improve VPN bioavailability and brain targeting via intranasal (IN) delivery. Methods: Different lipid-based NCs were developed and characterized for vesicle size, zeta potential, VPN entrapment efficiency (EE) and morphological characterization using transmission electron microscope (TEM). The prepared NCs were loaded into ISG formulations and characterized for their mucoadhesive properties. Ex-vivo permeation and histological study of the nasal mucosa were conducted. Pharmacokinetic and brain tissue distribution were investigated and compared to a marketed VPN product following administration of a single dose to rats. Results: VPN-D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) micelles nano-formulation showed the smallest particle size, highest EE among the studied NCs. TEM images revealed an almost spherical shape for all the prepared NCs. Among the NCs studied, VPN-loaded TPGS micelles demonstrated the highest percent cumulative VPN ex vivo permeation. All the prepared ISG formulations revealed the presence of mucoadhesive properties and showed no signs of inflammation or necrosis upon histological examination. Rats administered IN VPN-loaded TPGS-micelles ISG showed superior VPN concentration in the brain tissue and significant high relative bioavailability when compared to that received raw VPN-loaded ISG and marketed drug oral tablets. VPN-D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) micelles nano-formulation showed the smallest particle size, highest EE among the studied NCs. TEM images revealed an almost spherical shape for all the prepared NCs. Among the NCs studied, VPN-loaded TPGS micelles demonstrated the highest percent cumulative VPN ex vivo permeation. All the prepared ISG formulations revealed the presence of mucoadhesive properties and showed no signs of inflammation or necrosis upon histological examination. Rats administered IN VPN-loaded TPGS-micelles ISG showed superior VPN concentration in the brain tissue and significant high relative bioavailability when compared to that received raw VPN-loaded ISG and marketed drug oral tablets. Conclusion: VPN-loaded TPGS-micelles ISG formulation is a successful brain drug delivery system with enhanced bioavailability for drugs with poor bioavailability and those that are frequently administered.

Objective: Control the release and enhance the bioavailability of chitosan-doxazosin mesylate nanoparticles (DM-NPs). Significance: Improve DM bioavailability for the treatment of benign prostatic hyperplasia and hypertension. Methods: Plackett-Burman design was utilized to screen the variables affecting the quality of DM-NPs prepared by ionic gelation method. The investigated variables were initial drug load (X1), chitosan percentage (X2), tripolyphosphate sodium (TPP) percentage (X3), poloxamer percentage (X4), homogenization speed (X5), homogenization time (X6) and TPP addition rate (X7). The prepared DM-loaded NPs have been fully evaluated for particle size (Y1), Zeta potential (Y2), production yield (Y3), entrapment efficiency (Y4), loading capacity (Y5), initial burst (Y6), and cumulative drug release (Y7). Finally, DM pharmacokinetic has been investigated on healthy albino male rabbits by means of non-compartmental analysis. Results: The combination of variables showed variability of Y1, Y2, and Y3 equal to 122-710 nm, 3.49-23.63 mV, and 47.31-92.96%, respectively. While Y4 and Y5, reached 99.87%, and 8.53%, respectively. The prepared NPs revealed that X2, X3, and X4 are the variables that play the important role in controlling the release behavior of DM from the NPs. The in vivo pharmacokinetic results indicated the enhancement in bioavailability of DM by 7 folds compared to drug suspension and the mean residence time prolonged to 23.72 h compared to 4.7 h of drug suspension. Conclusion: The study proved that controlling the release of DM from NPs enhance its bioavailability and improve the compliance of patients with hypertension or benign prostatic hyperplasia.

To avoid the first-pass metabolism of avanafil (AVA) and its altered absorption in the presence of food after oral administration, this study aimed to investigate the potential of TPGS-based mixed micelle (MM)-loaded film for transdermal delivery and the enhancement of bioavailability. A Box–Behnken design was employed to optimize the permeation behavior of AVA from the transdermal film across the skin. The variables were the hydrophile-lipophile balance (HLB) of the surfactant (X1), the concentration of mixed micelles (MMs) in the film (X2), and the concentration of the permeation enhancer (X3). The initial permeation of AVA after 1 h (Y1), and the cumulative permeation of AVA after 24 h (Y2) were the dependent variables. Ex vivo studies were carried out on freshly isolated rat skin to investigate the drug’s permeation potential and results were visualized using a fluorescence laser microscope. Moreover, the pharmacokinetic behavior after a single application on male Wistar rats, in comparison with films loaded with raw AVA, was evaluated. The results showed that the optimum factor levels were 9.4% for the HLB of the surfactant used, and 5.12% MMs and 2.99% penetration enhancer in the film. Imaging with a fluorescence laser microscope indicated the ability of the optimized film to deliver the payload to deeper skin layers. Furthermore, optimized AVA-loaded TPGS-micelles film showed a significant increase (p &lt, 0.05) in the Cmax of AVA and the area under the AVA plasma curve (approximately three-fold). The optimized AVA-loaded TPGS-MM film thus represents a successful delivery system for enhancing the bioavailability of AVA.

This study aimed to enhance the dissolution of simvastatin (SMV) through its formulation in liquisolid tablets (LSTs) to improve its bioavailability and hypolipidemic activity after oral administration. SMV-LSTs were optimized using Box-Behnken design to maximize the rate and extent of SMV dissolution. The optimized SMV-LST was evaluated for pharmacokinetic parameters and potential hypolipidemic activity on induced hyperlipidemic rats. The dissolution parameters revealed a shortening of mean dissolution time from 10.99 to 6.82 min, increasing of dissolution rate during the first 10 min from 1253.15 to 1667.31 μg/min, and enhancing of dissolution efficiency after 60 min from 71.92 to 86.93% for SMV-LSTs versus the commercial SMV tablets. The obtained data reflected an improvement in the relative bioavailability of SMV with 148.232% which was confirmed by the significant reduction of the levels of circulating total cholesterol, triglycerides that reached the normal level after 12 h. In particular, the optimized SMV-LSTs reduced serum low-density lipoproteins (LDL) by 44.6% which was significantly different from the commercial SMV tablets. In contrast, the level of serum high-density lipoprotein (HDL) was significantly augmented after 4 h in rats treated with the optimized SMV-LSTs by 47.6%. Finally, the optimized SMV-LSTs showed a significant lower atherosclerotic index value which could maximize its potential in decreasing the risk of coronary disease and atherosclerosis. Overall enhancement in pharmacokinetics and pharmacodynamics in comparison with the commercial tablets confers the potential of the liquisolid approach as a promising alternative for improved oral bioavailability, hypolipidemic, and cardioprotective effects of SMV. Graphical abstract.

Rosuvastatin is a hypolipidemic drug of limited oral bioavailability. The aim was to develop rosuvastatin flexible chitosomes and loading into a pullulan-based tablet to improve the bioavailability and maximize the antihyperlipidemic and antioxidant activities. Chitosomes nanoparticles were developed and characterized. Pullulan-based lyophilized fast dissolving tablets were developed and evaluated. The tablets' outer and inner structures were morphologically investigated. In vivo disintegration of the prepared tablets was studied in healthy human volunteers. The pharmacokinetics, antihyperlipidemic, antioxidant, and biochemical markers activities were conducted after administration of the tablets into male Wister rats. Liver histopathology was also investigated. The prepared chitosomes illustrated an average particle size of 342.22 ± 2.90 nm, a zeta potential value of +28.87 ± 1.39 mV and a drug entrapment efficiency of 94.59 ± 1.62%. The developed tablets showed an acceptable quality control characteristics and in vivo disintegration time of 1.48 ± 0.439 min. Scanning electron microscopy revealed distinct porous surface and sponge-like inner structure. The chitosomes based tablets demonstrated higher relative bioavailability by more than 30% and 36% when compared with the corresponding pure rosuvastatin and the marketed drug tablets, respectively. Moreover, the chitosomes based tablets showed a significant improvement in the hepatic serum biomarkers and a dramatic decrease in the serum antioxidants in response to Poloxamer 407 intoxication. The prepared tablets did not exhibit marked histopathological changes in the hepatic tissues. Accordingly, the pullan-based lyophilized fast-dissolving tablets loaded with chitosomes nanoparticles could be considered as a promising drug formulation for enhancing rosuvastatin bioavailability and pharmacodynamics activity.

The aim of this work was to study the influence of process variables on the quality attributes of pomegranate extract loaded solid lipid nanoparticles (PE-SLNs) using Plackett–Burman design. PE-SLN formulations were prepared by hot homogenization followed by ultra-sonication technique and evaluated based on the dependent variables that were analyzed utilizing Statgraphics Centurion XV software. The lipid and surfactant (type and concentration), co-surfactant concentration, sonication time, and amplitude were selected as the independent variables (X1–X7). The dependent parameters were particle size, polydispersity index, zeta potential, entrapment efficiency, and cumulative drug release (Y1–Y5). Response surface plots, Pareto charts, and mathematical equations were generated to study the influence of independent variables on the dependent quality parameters. Out of seven variables, X1, X2, and X6 have the main significant (p value < 0.05) effect on the entrapment efficiency, the cumulative drug release, the polydispersity index, respectively, while particle size was mainly affected by X3, X6 and zeta potential by X1, X3, and X4. Consequently, this screening study revealed that stearic acid as lipid, Tween 80 as surfactant, as well as sonication with short time and high amplitude can be selected for the development of PE-SLN formulation with minimum particle size, maximum zeta potential, highest entrapment, and sustained drug release behavior. Meanwhile, concentrations of lipid, surfactant, and co-surfactant are planned to be scaled up for further optimization study. In conclusion, the Plackett–Burman design verified its influence and significance in determining and understanding both process and formulation variables affecting the quality of PE-SLNs.

Gout is the most familiar inflammatory arthritis condition caused by the elevation of uric acid in the bloodstream. Febuxostat (FBX) is the latest drug approved by the United States Food and Drug Administration (US FDA) for the treatment of gout and hyperuricemia. FBX is characterized by low solubility resulting in poor gastrointestinal bioavailability. This study aimed at improving the oral bioavailability of FBX by its incorporation into self-nanoemulsifying delivery systems (SNEDS) with minimum globule size and maximum stability index. The SNEDS-incorporated FBX was loaded into a carrier substrate with a large surface area and lyophilized with other excipients to produce a fluffy, porous-like structure tablet for the transmucosal delivery of FBX. The solubility of FBX was studied in various oils, surfactants, and cosurfactants. Extreme vertices design was utilized to optimize FBX-SNEDS, and subsequently loaded into lyophilized tablets along with suitable excipients. The percentages of the main tablet excipients were optimized using a Box&ndash, Behnken design to develop self-nanoemulsifying lyophilized tablets (SNELTs) with minimum disintegration time and maximum drug release. The pharmacokinetics parameters of the optimized FBX-SNELTs were tested in healthy human volunteers in comparison with the marketed FBX tablets. The results revealed that the optimized FBX-SNELTs increased the maximum plasma concentration (Cmax) and decreased the time to reach Cmax (Tmax) with a large area under the curve (AUC) as a result of the enhanced relative oral bioavailability of 146.4%. The significant enhancement of FBX bioavailability is expected to lead to reduced side effects and frequency of administration during the treatment of gout.

Osama AA Ahmed,1,2 Khalid M El-Say,1,3 Bader M Aljaeid,1 Shaimaa M Badr-Eldin,1,4 Tarek A Ahmed1,3 1Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Minia University, Minia, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt; 4Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt Background: Vinpocetine (VNP), a semisynthetic natural product, is used as a vasodilator for cerebrovascular and age-related memory disorders. VNP suffers from low oral bioavailability owing to its low water solubility and extensive first-pass metabolism. This work aimed at utilizing D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and alpha lipoic acid (ALA) to develop efficient micellar system for transdermal delivery of VNP. Materials and methods: VNP-TPGS-ALA micelles were prepared, characterized for particle size using particle size analyzer, and investigated for structure using transmission electron microscope. Optimization of VNP-TPGS-ALA micelles-loaded transdermal films was performed using Box–Behnken experimental design. The investigated factors were percentage of ALA in TPGS (X1), citral concentration (X2), and propylene glycol concentration (X3). Elongation percent (Y1), initial permeation after 2hours (Y2), and cumulative permeation after 24 hours (Y3) were studied as responses. Results: Statistical analysis revealed optimum levels of 16.62%, 3%, and 2.18% for X1, X2, and X3, respectively. Fluorescent laser microscopic visualization of skin penetration of the optimized transdermal film revealed marked widespread fluorescence intensity in skin tissue after 0.5, 2, and 4 hours compared with raw VNP transdermal film formulation, which indicated enhancement of VNP skin penetration. Conclusion: The obtained results highlighted the potentiality of VNP nanostructure-based films for controlling the transdermal permeation of the drug and improving its effectiveness. Keywords: bioavailability, box behnken design, citral, fluorescent laser microscope, nanostructured-based films, permeation

Self-nanoemulsifying delivery systems (SNEDs) are one of the most important approaches for increasing the solubilization and absorption of a drug. This study aimed to develop a system using fluvastatin (FLV) in SNEDs with minimum globule size to enhance cellular uptake and induce apoptosis in human colorectal cancer cells (HCT-116). Thirteen formulations of FLV-loaded SNEDs were prepared, analyzed, and optimized with the extreme vertices mixture design. The optimized formulation had globules 88.4 nm in size, and an IC50 of 23.38 ± 4.2 μM compared to 52.69 ± 6.6 μM for the raw drug. This optimized formulation was evaluated in HCT-116 cells for its cellular uptake, in vitro cytotoxicity, and the induction of apoptosis. The cellular uptake efficiency of FLV-loaded SNEDs was 47.9 ± 5.6% and 71.7 ± 10.2% after 2 and 4 h incubation times, respectively, which represents a three-fold increase over the raw drug efficiency. Cellular morphology and DNA fragments confirmed potentiation of apoptosis. These results indicate that loading FLV in SNEDs improves its cellular uptake and hence increases cytotoxicity, making this a promising approach for the treatment of patients with colorectal carcinoma.

To enhance the poor bioavailability and extensive liver metabolism of atorvastatin calcium (ATC), we have developed an oleic acid–reinforced PEGylated polymethacrylate (OLA–PEG–E-RLPO) transdermal film as a convenient and alternative delivery system. The effect of varying levels of Eudragit RLPO, PEG 400, and oleic acid on the target product profile was optimized through Quality by Design (QbD) approach. The ATC–loaded OLA–PEG–E-RLPO transdermal films were evaluated in ex-vivo experiments using full thickness skin, utilizing Franz cell studies, and undergone in-vivo pharmacokinetics/pharmacodynamics (PK/PD) assessment, using poloxamer-induced dyslipidemic Sprague-Dawley rats. At 2 and 12 h, the optimized ATC films with a thickness of 0.79 mm showed permeation of 37.34% and 97.23% into the receptor compartment, respectively. Steady-state flux was 0.172 mg/cm2h, with 7.01 × 10−4 cm/h permeability coefficient, and 0.713 × 10−3 cm2/h diffusion coefficient. In-vivo PK results indicated that the absorption profiles (AUC0-∞) of the optimized film in pre-treated group of animals were 8.6-fold and 2.8-fold greater than controls pre-treated with non-PEGylated non-oleic acid film and orally administered ATC, respectively. PD assessment of the lipid panel indicated that the lipid profile of the optimized film pre-treated group reached normal levels after 12 h, along with the significant enhancement over the non–PEGylated non-oleic acid film and the oral marketed tablet groups. The histopathological findings revealed near-normal hepatocyte structure for the optimized film pre-treated animal group. Our results further indicate that transdermal delivery films based on an optimized ATC–loaded OLA–PEG–E-RLPO were successfully developed and their assessment in both ex-vivo and in-vivo suggests enhanced permeability and improvement in bioavailability and antidyslipidemic activity of ATC. This approach can provide several advantages, especially during chronic administration of ATC, including improvement in patient compliance, therapeutic benefits, bioavailability, and feasibility for commercialization and as a platform for other drug classes.

Glimepiride (GMD) is a third-generation sulfonylurea derivative and one of the top three most-prescribed oral antidiabetic drugs. The need for a depot formulation exists, and a safe and effective antidiabetic therapy is the goal of this study. The aims were to design a depot in situ gel (ISG) formulation and investigate the main factors that control the initial burst and sustain the GMD effect using the Box-Behnken design. The studied factors were polymer percent (X1), plasticizer percent (X2) and benzyl benzoate percent in N-methyl-2-pyrrolidone (X3). The results revealed that X2 is the only factor that showed significant effects on all investigated responses. Scanning electron microscopy images showed that an increase in PEG % improved the smoothness and reduced the porosity of the ISG formulation surface. The GMD plasma levels in diabetic rats revealed no significant difference (p in situ forming system could be useful for improving patient compliance and diabetes treatment effectiveness.

Monoclonal antibodies (mAbs) are advantaged with high homogeneity and very specific antigen-binding capability. In the last 50 years, mAbs are widely utilized for their splendid therapeutic efficacy with markedly low side effects. Regarding cancer immunotherapy, checkpoints antibodies that delivered to their sites of action were proved to enhance vastly the body’s immune system to identify and solely exterminate cancer cells. Despite the challenges and complications faced due to the protein nature of these mAbs along with the lack of targeting ability, many successful formulations and delivery systems were raised and evidenced. In this chapter, an overview of the mAbs origin, types and new utilizations for diagnosis and treatment of many challenging diseases along with the diversity of the employed mAbs delivery systems are covered. Furthermore, the know-how of conquering the challenges provoked using these systems is critically illustrated and the clinical transition of several mAbs formulations from bench to bed is exampled by many of already approved formulations. Finally, many prospective systems like microfluidics and local delivery techniques of mAbs are also emphasized in this chapter.

Background Injectable in situ gel (ISG) systems suffer from high initial drug release that may result in toxic effects. Objective This work aimed to develop an injectable sustained release rosuvastatin (RSV) ISG formulation with minimum initial drug burst and improved hyperlipidemic efficacy. Methods Six formulation factors that affect RSV release after 0.5, 2 and 24 hrs have been screened and the significant ones were optimized utilizing an experimental design tool. The optimum ISG formulation components were physicochemically characterized. Kinetic treatment, dissolution efficiency and mean dissolution time were investigated for the developed ISG formulations. Pharmacodynamic effects of the optimized ISG formulation were studied and compared to ISG formulation loaded with free RSV and to a marketed oral drug product. Results The concentration polylactide-co-ε-caprolactone (25: 75), the surfactant hydrophilic lipophilic balance (HLB) and the ratio of surfactant to polyethylene glycol 400 were significantly affecting the release of RSV during the first 24 h. Physicochemical characterization demonstrated complete dispersion of RSV in the polymeric matrix with slight changes in the drug crystalline structure. The optimized formulation demonstrated acceptable syringeability, good flow rate and was able to extend the in vitro drug release for 34 days. The ISG formulations complied with Weibull model. Pharmacodynamic study revealed a sustained reduction in the lipid profile that lasted for 21 days with a marked decrease in the lipid level during the first 24 hrs from the ISG system loaded with free RSV. Conclusion The optimized RSV ISG formulation could be considered a promising strategy due to a reduction in dosing frequency and enhancement in hypolipidemic efficacy.

Background: Vinpocetine (VPN) is a synthetic derivative of the Vinca minor alkaloids. The drug is characterized by a short half-life, limited water solubility and high hepatic first-pass effect. The objective was to develop different lipid-based nanocarriers (NCs) loaded into a thermosensitive in situ gelling (ISG) system to improve VPN bioavailability and brain targeting via intranasal (IN) delivery. Methods: Different lipid-based NCs were developed and characterized for vesicle size, zeta potential, VPN entrapment efficiency (EE) and morphological characterization using transmission electron microscope (TEM). The prepared NCs were loaded into ISG formulations and characterized for their mucoadhesive properties. Ex-vivo permeation and histological study of the nasal mucosa were conducted. Pharmacokinetic and brain tissue distribution were investigated and compared to a marketed VPN product following administration of a single dose to rats. Results: VPN-D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) micelles nano-formulation showed the smallest particle size, highest EE among the studied NCs. TEM images revealed an almost spherical shape for all the prepared NCs. Among the NCs studied, VPN-loaded TPGS micelles demonstrated the highest percent cumulative VPN ex vivo permeation. All the prepared ISG formulations revealed the presence of mucoadhesive properties and showed no signs of inflammation or necrosis upon histological examination. Rats administered IN VPN-loaded TPGS-micelles ISG showed superior VPN concentration in the brain tissue and significant high relative bioavailability when compared to that received raw VPN-loaded ISG and marketed drug oral tablets. VPN-D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) micelles nano-formulation showed the smallest particle size, highest EE among the studied NCs. TEM images revealed an almost spherical shape for all the prepared NCs. Among the NCs studied, VPN-loaded TPGS micelles demonstrated the highest percent cumulative VPN ex vivo permeation. All the prepared ISG formulations revealed the presence of mucoadhesive properties and showed no signs of inflammation or necrosis upon histological examination. Rats administered IN VPN-loaded TPGS-micelles ISG showed superior VPN concentration in the brain tissue and significant high relative bioavailability when compared to that received raw VPN-loaded ISG and marketed drug oral tablets. Conclusion: VPN-loaded TPGS-micelles ISG formulation is a successful brain drug delivery system with enhanced bioavailability for drugs with poor bioavailability and those that are frequently administered.

This research purposed to formulate an optimized imatinib mesylate (IM)–loaded niosomes to improve its chemotherapeutic efficacy. The influence of 3 formulation factors on niosomal vesicular size (Y 1 ), zeta potential (Y 2 ), entrapment capacity percentage (Y 3 ), the percentage of initial drug release after 2 h (Y 4 ), and the percentage of cumulative drug release after 24 h (Y 5 ) were studied and optimized using Box-Behnken design. Optimum desirability was specified and the optimized formula was prepared, stability tested, morphologically examined, checked for vesicular bilayer formation and evaluated for its in vitro cytotoxicity on 3 different cancer cell lines namely MCF-7, HCT-116, and HepG-2 in addition to 1 normal cell line to ensure its selectivity against cancer cells. The actual responses of the optimized IM formulation were 425.36 nm, −62.4 mV, 82.96%, 18.93%, and 89.45% for Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 , respectively. The optimized IM-loaded niosomes confirmed the spherical vesicular shape imaged by both light and electron microscopes and further proven by differential scanning calorimetry. Moreover, the optimized formula exhibited improved stability on storage at 4 ± 2°C and superior efficacy on MCF7, HCT-116, and HepG2 as IC 50 values were 6.7, 16.4, and 7.3 folds less than those of free drug, respectively. Interestingly, IC 50 of the optimized formula against normal cell line was ranged from 3 to 11 folds higher than in different cancer cells indicating a higher selectivity of the optimized formula to cancer cells. In conclusion, the incorporation of IM in niosomes enhanced its efficacy and selectivity toward cancer cells, presenting a promising tool to fight cancer using this approach.